Cancer stem cell drugs target K-ras signaling in a stemness context
| Autor: | Ernest Lacey, Tero Aittokallio, Camilo Guzmán, Benoit Lectez, Arafath Kaja Najumudeen, Elina Siljamäki, Alok Jaiswal, Itziar M. D. Posada, Christina Oetken-Lindholm, Daniel Abankwa |
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| Přispěvatelé: | Institute for Molecular Medicine Finland, Tero Aittokallio / Principal Investigator, Bioinformatics |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Sesterterpenes PROTEINS Context (language use) Biology Bioinformatics Caveolae Molecular oncology Proto-Oncogene Proteins p21(ras) 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Growth factor receptor Calmodulin Cancer stem cell Neoplasms Genetics medicine Humans CAVEOLIN-1 MEMBRANE ORIENTATION PHOSPHATIDYLSERINE Molecular Biology Oxazoles Salinomycin GENE-EXPRESSION Pyrans SALINOMYCIN IDENTIFICATION NANOCLUSTERS Cancer Cell cycle medicine.disease 3. Good health Gene Expression Regulation Neoplastic 030104 developmental biology chemistry 030220 oncology & carcinogenesis PLASMA-MEMBRANE Cancer cell Cancer research MCF-7 Cells Neoplastic Stem Cells ras Proteins Original Article 3111 Biomedicine RESISTANCE |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | Cancer stem cells (CSCs) are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. Salinomycin is the most established CSC inhibitor. However, its primary mechanistic target is still unclear, impeding the discovery of compounds with similar anti-CSC activity. Here, we show that salinomycin very specifically interferes with the activity of K-ras4B, but not H-ras, by disrupting its nanoscale membrane organization. We found that caveolae negatively regulate the sensitivity to this drug. On the basis of this novel mechanistic insight, we defined a K-ras-associated and stem cell-derived gene expression signature that predicts the drug response of cancer cells to salinomycin. Consistent with therapy resistance of CSC, 8% of tumor samples in the TCGA-database displayed our signature and were associated with a significantly higher mortality. Using our K-ras-specific screening platform, we identified several new candidate CSC drugs. Two of these, ophiobolin A and conglobatin A, possessed a similar or higher potency than salinomycin. Finally, we established that the most potent compound, ophiobolin A, exerts its K-ras4B-specific activity through inactivation of calmodulin. Our data suggest that specific interference with the K-ras4B/calmodulin interaction selectively inhibits CSC. |
| Databáze: | OpenAIRE |
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